Asthma is a disease which is becoming more prevalent and is the most common disease of childhood. It can be identified by recurrent wheeze and intermittent air flow limitation. Despite many advances in its understanding, said pathology remains a poorly understood and often poorly treated disease. Previously, contraction of airway smooth muscles has been regarded as the most important feature of asthma. Recently there has been a marked change in the way asthma is managed, stemming from the fact that asthma is recognized as a chronic inflammatory disease. Uncontrolled airway inflammation may lead to mucosal damage and structural changes giving irreversible narrowing of the airways and fibrosis of the lung tissue. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation.
Another respiratory disease whose incidence is steadily increasing throughout the world is chronic obstructive pulmonary disease (COPD). Most patients with COPD have acquired their lung disease through smoking cigarettes. Depending upon trends in tobacco smoking, it is set to rise to fifth most prevalent cause of disability, worldwide by 2020 (Leckie M et al Exp Opin Invest Drugs 2000, 9, 3-23).
Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema.
Chronic bronchitis is characterized by excessive secretion of bronchial mucus, whereas emphysema denotes abnormal, permanent enlargement of air spaces distal to the terminal bronchiole, with destruction of their walls and without obvious fibrosis (American Toracic Society). Each condition is treated as specific diseases.
Chronic obstructive bronchiolitis is due to obstruction of the peripheral airways as a result of inflammation in the bronchioles.
β2-Adrenoceptor agonists have been the mainstay of treatment for asthma for many years in view of their prompt bronchodilation effects. Previous researches have also shown that β2-agonists have potent anti-inflammatory capabilities, e.g. represented by suppression of release of the pro-inflammatory cytokines.
The first generation drugs such as salbutamol or fenoterol were characterized by a relatively short duration of action which has been considered as a disadvantage particularly for patients with nocturnal asthma. Moreover, they have limited effects in COPD, since this disease involves ‘irreversible’ airways obstruction. The development of longer acting β2-agonists such as formoterol, salmeterol and TA 2005 has therefore been heralded as a major new development in the treatment of asthma. According to some authors, long-acting β2-agonists (LABAs) may have acute anti-inflammatory activity in vivo (Johnson M Clin Exp Allergy 1992, 22, 177-181; Stelmach I et al Ann Allergy Asthma Immunol 2002, 89, 67-73). These drugs are a new interesting therapeutic option for patients with chronic obstructive pulmonary disease (COPD) as well since they have been shown to significantly improve lung function and symptom control.
β2-Adrenergic agonists can also stimulate alveolar fluid clearance in several animal species and in ex vivo rat and human lungs. In view of these findings beta-adrenergic agonist therapy has been proposed as a possible treatment for accelerating the resolution of pulmonary oedema in patients with acute pulmonary oedema (Sacuma T et al Am J Respir Crit Care Med 1997, 155, 506-512). Treatment with β2-agonists may also increase the secretion of surfactant and perhaps exert an anti-inflammatory effect, thus helping to restore vascular permeability of the lung (Ware L et al New Eng. J Med 2000, 342, 1334-1349.
Drugs intended for the treatment of lung diseases such as asthma and COPD are currently administered by pulmonary delivery which relies on inhalation of an aerosol through the mouth and throat so that the drug substance can reach the lung. They can be administered as aqueous or hydroalcoholic formulations through a nebuliser, as dry powders by means of Dry Powder Inhalers or in halogenated hydrocarbon propellants. The propellant-based systems require suitable pressurized metered-dose inhalers (pMDIs) which release a metered dose of medicine upon each actuation. The relevant formulations can be in the form of solutions or suspensions. Solution formulations, with respect to suspensions, do not present problems of physical stability of the suspended particles and so could guarantee a higher dose uniformity and reproducibility. As far as the type of propellant is concerned, hydrofluoroalkanes [(HFAs) known also as hydro-fluoro-carbons (HFCs)] would be mandatory propellants as chlorofluorocarbons (known also as Freons or CFCs), which were for many years the preferred propellants aerosols for pharmaceutical use, have been implicated in the destruction of the ozone layer so their use is being phased out. In particular, 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of pharmaceutical aerosol formulations using such HFA propellant systems have been disclosed.
In developing a therapeutic aerosol, the aerodynamic size distribution of the inhaled particles is the most important variable in defining the site of droplet or particle deposition in the lungs of the patient; in short, it will determine whether drug targeting succeeds or fails. See P. Byron, “Aerosol Formulation, Generation, and Delivery Using Nonmetered Systems,” Respiratory Drug Delivery, 144-151,144 (CRC Press, 1989).
Thus, a prerequisite in developing a therapeutic aerosol is a preferential particle size.
When the formulation is in the form of suspension, the particle size of the cloud is dominated by the particle size of the suspended drug, defined by the milling/micronization process. When the formulation is in the form of solution, the volumetric contribution of suspended drug particles is absent and much finer liquid droplets clouds, largely defined by the drug concentration in the solution, are generated.
Solid particles and/or droplets in an aerosol formulation can be characterized by their mass median aerodynamic diameter (MMAD, the diameter around which the mass aerodynamic diameters are distributed equally).
Particle deposition in the lung depends largely upon three physical mechanisms:                i) impaction, a function of particle inertia;        ii) sedimentation due to gravity; and        iii) diffusion resulting from Brownian motion of fine, submicrometer (<1 microns) particles. The mass of the particles determines which of the three main mechanisms predominates.        
For aerosol therapy of drugs which topically act on the smooth muscle of the conducting airways, and in particular for β2-agonists, it has been reported in the past that particles should preferentially deposit in the upper- to mid-pulmonary region (bronchiole region), so they should have a MMAD of about 1.5(2.0) to about 5.0 microns, preferably approximately 3 microns (Zanen P et al Int J Pharm 1994, 107, 211-217; Int J Pharm 1995, 114, 111-115; Thorax, 1996, 51, 977-980).
In fact, particles having aerodynamic diameters of greater than about 5 microns generally do not reach the lung since they tend to impact the back of the throat and are swallowed and possibly orally absorbed, while particles smaller than 1.5 (2.0) micron, i.e., about 0.5 to about 2 microns, capable of reaching the alveolar region, have been considered undesirable because they can be absorbed into the bloodstream and might enhance the undesired systemic effects of the drugs. Particles having diameters smaller than about 0.5 microns have been generally considered as not therapeutically useful as they can be exhaled.
Accordingly, pMDI formulations of β2-agonist have traditionally been formulations able to deliver particles whose larger fraction is comprised between 2 and 5 microns and the amount of those below 1 micron is very limited since the former are small enough to reach the upper- to mid-pulmonary region, but are too large to reach the alveoli. This is also the inherent particle size of the formulation in the form of suspensions as conventional micronization (air-jet milling) of pure drug substance can reduce the drug particle size to about 2-3 microns.
On the other hand, it is known that the density of the beta-adrenergic receptors is higher in the distal tract of the bronchioles (Barnes P et al Am Rev Respir Dis 1983, 127, 758-762), a region which is better reached by smaller particles. Moreover inflammation in asthma in not merely confined to the large central airways but also extends to small peripheral airways. The eosinophilic inflammation process which has been seen to be associated to asthma concerns both the bronchial and the alveolar districts (Wang S J Immunol 2001, 166, 2741-2749). Recently, Martin R in J Allergy Clin Immunol 2002, 109 (Suppl 2), 447-460 reported that distal lung diseases appear to increase the risk of recurrent asthma exacerbation, while disease-related anatomic changes in the small airways of the distal lung are prominent in fatal asthma. In this respect, in his opinion, the administration of drug with particles of a diameter of about 1 micron (referred as “extrafine” aerosols) could be advantageous. The clinical significance of distal lung disease makes this region an important therapeutic target so particles able to reach and deposit into such region could better contribute to the management of the disease. It has been also reported that, among the particles smaller than 0.5 micron, those with a diameter less or equal than 0.3 micron, preferably between 5 and 300 nm, can be deposited in the alveolar region of the lung by sedimentation. This range of particle has been referred to in the literature as “ultrafine” particles.
“Ultrafine” particles generated from di-2-ethylhexyl sebacate (DEHS) as a model, have also been reported to have a good airway penetration (Anderson P et al Chest 1990, 97, 1115-1120). Therefore medicinal aerosol particles having a diameter <0.1 μm can be particularly effective in case of airway obstruction in asthmatic subjects wherein the pathology is associated with mucus hypersecretion which hinders the diffusion of the drug or in patients affected by obstructive lung diseases such as COPD. Intuitively indeed, one would expect the reduction in the lumen of airways by mucus and permanent constriction would require finer clouds for perfusion.
In virtue of the inherent anti-inflammatory properties of LABAs, relevant formulations capable of delivering a significant fraction of fine particles would be expected to be of great advantage in patients affected by broncho-pulmonary obstructive diseases. Amirav I et al in J Nucl Med 2002, 43, 487-491 emphasize the need for improvement in aerosol delivery by targeting narrow peripheral airways with superfine aerosols in the treatment of inflammation airways diseases and in particular in acute bronchiolitis.
Formoterol, {(R,R)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl]-phenyl]formamide} is a selective β2-receptor agonist, exerting, upon inhalation, a prolonged bronchodilation up to 12 hours. It is currently marketed as CFC formulation (Foradil®).
In view of the above considerations, it would be highly advantageous to provide highly efficient formoterol formulation to be administered by pMDI characterized by a deeper lung penetration wherein, unexpectedly, the systemic exposure is not significantly higher than that of the formulations currently on the market.